Intermediates for synthesis of vinblastine compound and method for synthesizing the intermediate

ABSTRACT

Intermediates A, which are important in the whole synthesis of vindoline; and a method of synthesizing intermediates respectively represented by the general formulae B and C. By the method, the target intermediates are effectively synthesized with satisfactory reproducibility. This synthesis method is especially suitable for mass production. General formula A General formula B General formula C

FIELD OF THE INVENTION

[0001] The present invention relates to a compound represented bygeneral formula A, which is useful as intermediate at the totalsynthesis of vindoline,

[0002] (in the formula, R¹ is one selected from the group consisting ofH, OH, alkoxy group, substituted or non-substituted benzenesulfonyloxygroup, and alkylsulfonyloxy group, R² is 1,1-dimethylethoxycarbonyl[(1,1-Dimethylethoxy)carbonyl, Boc] group or acetyl group, R³ is alkylgroup, R⁴ is benzyl or substituted benzyl group. R⁵ is H,tetrahydropyranyl (THP) group, ethoxyethyl group, methoxymethyl group,acetyl group, benzoyl group, trialkylsilyl group or alkyldiarylsilylgroup.), alkyl acrylates represented by general formula B, which isimportant an intermediate at the total synthesis of vindoline,

[0003] [in the formula, R¹ is one selected from the group consisting ofH, OH, alkoxy group, substituted or non-substituted benzene sulfonyloxygroup, and alkyl sulfonyloxy group, R² is 1,1-dimethylethoxycarbonyl(indicated as Boc in a constitutional formula) group or acetyl groupand, R³ is alkyl group. R⁵ is H, tetrahydropiranyl (THP) group,ethoxyethyl group, methoxymethyl group, acetyl group, benzoyl group,trialkylsilyl group or alkyldiarylsilyl group.], especially relates toan effective method for synthesis of indole derivatives possessing amethyl acrylate group having good reproducibility and suited to massproduction, and an effective method for production of substitutedquinolines represented by general formula C, which is useful for thesynthesis of said general formula A, and whose regioselectivity andyield are improved.

[0004] (R₁, R₂ and R₃ are independently selected from the groupconsisting of H, OH, alkoxy group, alkyl, amino, amide and halogen.)

BACKGROUND OF THE INVENTION

[0005] Natural vinblastine (1) extracted from a plant belonging toApocynaciae is an antitumor agent which is currently used as a clinicalmedicine. However, since this agent shows a strong side effects, thedevelopments for a new congeners are broadly carried out in Japan oroutside of Japan.

[0006] The inventors of the present invention has already reported theart referring to the total synthesis of vindoline which consists a half(lower side) of vinblastine (1) used for the synthesis of abovementioned vinblastine and its congeners. However, for the totalsynthesis of vindoline, syntheses of various intermediates arenecessary, the improvements of the reproducibility of each processes andyield are needed, and the further improvement for process suited to theproduction concerning the commercial scale is needed.

[0007] Usually, the compound represented by said general formula B,which is the important intermediate for the synthesis of vindoline, wassynthesized using the derivatives of above mentioned general formula A,whose substituent at 2-position is replaced with iodine, as the startingmaterial by palladium-catalyzed coupling reaction with tin compound asshown in the following Schema 1 [S. Kobayashi, T. Ueda, T. Fukuyama,Synlett., 883-886 (2000)].

[0008] However, by above mentioned reaction, it is difficult toaccomplish the reaction in good yield and with good reproducibility, andfurther, in above mentioned reaction, there is a problem that the usesof agents such as toxic arsenic compound or carcinogeichexamethyltriamidephosphate (HMPA) are necessary. Therefore, theestablishment of the method for synthesis of above mentionedintermediate B characterizing not including above mentioned technicalproblems was desired. Further, as one intermediate for the synthesis ofabove mentioned intermediate A, quinolines represented by generalformula C, namely, substituted quinoline which has a substituted groupon benzene ring and does not have a substituted group on pyridine ringis used. As the typical well-known method for synthesis for asubstituted quinoline which has a substituted group on benzene ring, amethod for synthesis named Skraup quinoline synthesis which obtainsquinoline by heating anilines, glycerin and oxidant under the presenceof strong acid such as sulfuric acid can be mentioned [R. H. F. Manske,M. Kulka, Org. React. 28, 59-98 (1953)]. However, since said methodneeds a process to react by high temperature using strong acid, manybyproducts are generated besides the aimed compound. Therefore, verycomplicated separation and purification process is necessary to obtainthe aimed product and the yield by said method is not always good.Further, in a synthetic reaction of substituted quinoline which usesmeta substituted aniline or 2,3-disubstituted aniline as a startingmaterial, mixture of 5-substituted quinoline and 7-substitutedquinoline, or mixture of 6,7-substituted quinoline and 5,6-substitutedquinoline, which are regioisomers are generated. In the case of saidmixture, sometimes one isomer has predominant over another isomer at thegeneration by maximum four times amount according to the substitutioneffect, however, in general, the regioselectivity of the reaction is notso high, and this point is pointed out as a problem [M. H. Palmer, J.Chem. Soc., 3645-3652 (1962)]. Still more, the yield is also not sogood.

[0009] Furthermore, the compound represented by above mentioned generalformula C is the compound used as the synthetic intermediate of generalformula A, which are the intermediate at the total synthesis ofvindoline. And, for the establishment of effective synthetic process forthe total synthesis of vindoline, the improvement of the intermediateprocesses composing total synthesis is very important. Especially, theestablishment of the method producing substituted quinolines, which havea substituted group on benzene ring alone and do not have a substitutedgroup on pyridine ring, with improved regioselectivity has been stronglydesired.

[0010] Therefore, the first object of the present invention is toprovide a method for production of the intermediate B represented bygeneral formula B, which dissolves the problem of above mentionedconventional art has, having good yield and reproducibility, andfurther, said method should be applicable to the production process ofcommercial scale. The inventors of the present invention have conductedan eager study to investigate the method for production of the compoundrepresented by general formula B not by way of 2-iodoindole shown in theconventional art, and to establish the method for production by way ofcompound represented by general formula A. Thus the first object of thepresent invention is accomplished.

[0011] The second object of the present invention is to provide a methodfor the production of substituted quinolines by which the problems inconventional method for production of substituted quinolines have areimproved. The inventors of the present invention have investigated thecase to obtain the aimed compound represented by general formula C fromsubstituted aniline by way of cyclization reaction, and have found outthat the regioselectivity and the yield can be remarkably improved byusing following process. Namely, as the first, sulfonamide derivative ofabove mentioned substituted aniline is prepared, then acrolein is addedand a precursor for cyclization reaction is prepared and the precursoris used. The second object of the present invention is accomplished byuse of the compound represented by general formula D at the cyclizationreaction.

DISCLOSURE OF THE INVENTION

[0012] The first one of the present invention is the compoundrepresented by general formula A which is useful as the intermediate atthe total synthesis of vindoline.

[0013] The second one of the present invention is a method for synthesisof indole derivatives which are useful for the synthesis of vindolinerepresented by general formula B comprising, hydrogenation of thecompound represented by general formula A, transforming benzyl ester tocarboxylic acid, then formation of an acrylic acid alkyl ester unit byMannich reaction accompanied by decarboxylation under the condition ofMannich reaction. Desirably, the second one of the present invention isthe method for synthesis of indole derivatives which are useful for thesynthesis of vindoline represented by general formula B comprising,using a palladium on carbon catalyst prepared by loading palladium onactivated carbon as a hydrogenation catalyst.

[0014] The third one of the present invention is a method for synthesisof the substituted quinolines represented by above mentioned generalformula C by reacting substituted aniline sulfonamide compoundsrepresented by general formula E,

[0015] (wherein R₁, R₂ and R₃ is selected independently from the groupconsisting of H, OH, alkoxy group, alkyl group, amino group and halogen,R₄ is an alkyl group such as methyl group or substituted benzene, forexample, p-tolyl group) in alcohol containing acrolein and triethylamineso as to synthesize aldehyde intermediate represented by general formulaD, then cyclizating said aldehyde intermediate bytrifluoromethanesulfonic acid [TfOH: CF₃(SO₂)OH] or under the acidiccondition (acidification by hydrochloric acid or sulfuric acid) andobtaining dihydroquinoline derivatives represented by general formula F,

[0016] then treating the obtained dihydroquinoline derivative in MOH (Mis Na or K) in DMSO, and obtaining the substituted quiloline representedby general formula C. Desirably, R₁ is a substitution group of7-position and R₂ is a substitution group of 6-position, and eachsubstituted group is respectively selected from the group consisting ofH, hydroxyl group, alkoxy group and halogen independently and R₃ is H.Further, more desirably, the present invention is the method forsynthesis of said substituted quinoline, wherein the cyclizationreaction is carried out in tetrahydrofuran solution in whichhydrochloric acid of stronger than 3N is contained.

[0017] The present invention will be illustrated more in detail.

[0018] 1-1. At the first, the preparation example of the startingcompound represented by general formula A is shown.

[0019] In said general formula A, the compound of R¹=MsO, R²=Boc, R³=Me,R⁴=Bn and R⁵=THP can be effectively synthesized by using quinolinederivative whose hydrogen of hydroxyl group located on 7-position issubstituted by alkylsulfonyl group or arylsulfonyl group as a startingmaterial. For example, phenylisothiocyanate having α,β-unsaturatedaldehyde is obtained by ring-opening reaction (THF/H₂O mixed solution ofNa₂CO₃) of 7-mesyloxyquinoline with thiophosgene (CSCl₂) and aldehyde isreduced to alcohol and protected. Then thioamide compound is synthesizedby nucleophilic addition reaction of derivatives of malonic acid (intetrahydrofuran solution of NaH, benzylmethyl malonate is cooled byice-bath), and the obtained thioamide compound is reacted (in the argonatmosphere) at the temperature of 80° C. in toluene solution oftri-n-butyltin hydride (n-Bu₃SnH) and 2,2′-azobisisobutyronitrile(AIBN). After cooled down to room temperature, saturated KF solution isadded and the resulted mixture was stirred at room temperature, and thendiluted with ethyl acetate. After washing with brine, organic layer isdried over magnesium sulfate anhydride and solvent is removed by vacuum.Then the residue is subjected to a silica gel column chromatography andby elution with n-hexane:ethylacetate=2:1 mixed solvent, thus indolederivative compound 1 is obtained.

[0020] 1-2. The dichloromethane solution of said compound, di-t-butyldicarbonate, and triethylamine is cooled with ice-bath and4-(dimethylamino)pyridine is added, then the temperature is elevated tothe room temperature and stirred for 1 hour. The reaction mixture isdiluted by ethyl acetate. After washing with brine, organic layer isdried over magnesium sulfate anhydride and solvent is removed by vacuum.Then the residue is subjected to a silica gel column chromatography andby elution with n-hexane:ethylacetate=2:1 mixed solvent, thus thestarting material compound of general formula A, especially the startingmaterial characterizing R¹=MsO, R²=Boc, R³=Me, R⁴=Bn and R⁵=THP in thecompound of general formula A, can be obtained. Other compoundsrepresented by general formula A can be synthesized by the similarmethod.

[0021] 1-3. As the hydrogen source at the synthesis of the compound ofgeneral formula B from the compound of general formula A, ammoniumformate, cyclohexene or 1,4-cyclohexadiene can be used instead ofhydrogen. As a solvent, lower alcohol such as methanol or ethanol, orethyl acetate can be used. As a catalyst for hydrogenation, palladium oncarbon catalyst, palladium hydroxide or Raney nickel can be used, and asthe desirable one, palladium on carbon catalyst can be mentioned.

[0022] 1-4. Mannich reaction can be carried out by using a combinationof formalin, dimethylamine hydrochloride, acetic acid and sodiumacetate, a combination of formalin with dimethylamine hydrochloride, acombination of formalin and diethylamine with acetic acid, a combinationof formalin and inorganic acid e.g. hydrochloric acid with secondaryamine e.g. pyrrolizine. As the desirable combination, the combination.of formalin, dimethylamine hydrochloride, acetic acid and sodium acetatecan be mentioned.

[0023] 2-1. The compound of general formula E used in the presentinvention can be obtained by reacting substituted aniline withpara-toluenesulfonyl chloride (pTsCl) or methanesulfonyl chloride (MsCl)in dichloromethane in the presence of pyridine.

[0024] Instead of using pyridine in dichloromethane, it is possible touse M₂CO₃ (M is Na or K) in 1,4-dioxane/water mixed solvent.

[0025] 2-2. The compound of general formula D can be synthesized fromthe compound of general formula E by Michael addition reaction toacrolein (2-10 equivalents) in alcohol e.g. methanol in whichtriethylamine (0.1-2 equivalents) exists, in approximately 100% yield.

[0026] In this case, tertiary alkylamine such as diisopropylethylamine,diazabicycloundecene or diazabicyclononen can be used instead oftriethylamine.

[0027] 2-3. Substituted dihydroquinoline represented by general formulaF can be obtained by carrying out the cyclization reaction of thecompound represented by general formula D in dichloromethane solution oftrifluoromethanesulfonic acid or in tetrahydrofuran (THF) or 1,4-dioxanesolution of hydrochloric acid or sulfuric acid.

[0028] 2-4. The compound of general formula C, which is the aimedcompound of the present invention, can be obtained by treating mentionedobtained compound of general formula F by heating (at approximately 50°C. to 140° C.) in dimethylsufoxide (DMSO) in which MOH (M is Na or K)exists.

EXAMPLES

[0029] The synthetic intermediates for synthesis of vinblastine and itscongeners of the present invention and the method for synthesis of saidintermediates are illustrated according to the substantial Examples,however, not intending to limit the scope of the claims of the presentinvention.

Example 1

[0030] In the present Example, the method for synthesis of compound 2,characterizing R₁ of 7-position of general formula C is substituted by ahydroxyl group is illustrated.

[0031] Process 1

[0032] To a pyridine solution (470 mL) of 3-aminophenol (102.6 g, 0.940mol is added dropwise pyridine solution (500 mL) of p-toluenesulfonylchloride (shortened to TsCl) (198 g, 0.987 mol) over 3 hours withcooling with ice-bath. After stirring for 30 minutes maintaining sametemperature, the reaction mixture is diluted with ethyl acetate, thenwashed with brine. The water layer is extracted by ethyl acetate, theorganic layer is dried over magnesium sulfate anhydride. The solvent isremoved by vacuum. In order to remove remaining pyridine the obtainedresidue is diluted with ether and washed with 1N hydrochloric acid. Theorganic layer is neutralized, washed with brine, and dried overmagnesium sulfate anhydride. Solvent is condensed and removed by vacuumto give the starting material N-p-tosyl-3-hydroxyaniline (hereinaftershortened to compound 3).

[0033] Physical Property:

[0034] IR (film, cm⁻¹): 3260, 1600, 1493, 1304, 1149, 1091, 982, 690,565, 543.

[0035]¹H NMR (400 MHz, DMSO-d₆): δ 2.30 (3H, s), 6.39 (1H, d, J=8.0 Hz),6.52 (1H, d, J=7.6 Hz), 6.96 (1H, t, J=7.6 Hz), 7.32 (2H, d, J=7.6 Hz),7.64 (2H, d, J=8.8 Hz), 9.43(1H, bs, NH), 10.1 (1H, bs, OH).

[0036]¹³C NHR (100 MHz, DMSO-d₆): δ 21.0, 106.9, 110.6, 116.2, 126.8,129.7, 129.9, 136.9, 139.2, 144.4, 157.9.

[0037] Analysis: Calculated data for C₁₃H₁₃NO₃S: C, 59.30; H, 4.98; N,5.32.

[0038] Measured data: C, 59.14; H, 5.05; N, 5.30.

[0039] Process 2

[0040] In argon atmosphere, to the methanol solution (MeOH) (3.6 L)containing compound 3 (330 g, 0.940 mol) and triethylamine (144 ml,1.034 mol), which is cooled with ice-bath, acrolein (330 ml, 4.7 mol) isadded dropwise slowly. After the reaction completes, the reactionmixture is diluted with ethyl acetate and washed with brine. The organiccomponent is extracted from the water layer with ethyl acetate twotimes, and the obtained organic layers are combined, and then methanolis evaporated by vacuum at lower temperature. The remained organic layeris dried over magnesium sulfate anhydride. The solvent is condensed andremoved by vacuum to obtain3-(N-3-hydroxyphenyl-N-p-tosylpropionaldehyde) (hereinafter shortened tocompound 4). Said reaction can be indicated by the following scheme.

[0041] Physical Property

[0042] IR (film, cm⁻¹) 3430, 3029, 2736, 1720, 1595, 1483, 1455, 1343,1218, 1161, 1089, 970, 814, 755, 693, 658, 577, 550.

[0043]¹H NMR (400 MHz, CDCI3):δ 2.42 (3H, s), 2.68 (2H, t, J=7.2 Hz),3.85 (2H, t, J=7.2 Hz), 6.46 (1H, d, J=8.0 Hz), 6.70 (1H, s), 6.80 (1H,d, J=8.0 Hz), 7.13 (1H, t, J=8.0 Hz), 9.70 (1H, s, OH).

[0044]¹³C NMR (100 MHz, CDCI₃):δ 21.5, 42.8, 44.6, 50.8, 115.7, 116.6,119.8, 127.7, 129.6, 130.0, 134.5, 139.7, 143.9, 156.6, 200.4.

[0045] Process 3

[0046] To a tetrahydrofuran (THF) solution (1.8 L) of the compound 4(375 g, 0.940 mol) is added hydrochloric acid of 3 N (1.8 L) slowly, andthe mixture is stirred at 60° C. for 30 minutes. After reactioncompletes, the reaction mixture is neutralized by addition of sodiumbicarbonate during cooling with ice-bath. The reaction mixture isdiluted with ethyl acetate, and then washed with brine. The obtainedorganic layer is dried over magnesium sulfate anhydride, and thesolution is condensed by vacuum to obtain 7-hydroxy-1,2-dihydroquinoline derivative (hereinafter, shortened to compound 5).Said reaction can be indicated by the following scheme.

[0047] Physical Property

[0048]¹H NMR (400 MHz, CDCl³): δ 2.35 (3H, s), 4.41 (2H, dd, J=2.0, 4.0Hz), 5.44 (1H, dt, J=4.0, 9.6 Hz), 5.98 (1H, d, J=9.6 Hz), 6.69 (1H, dd,J=2.0, 4.0 Hz), 7.08 (2H, d, J=8.8 Hz), 7.25 (1H, s), 7.35 (2H, d, J=8.0Hz).

[0049]¹³C NMR (100 MHz, CDCl₃):δ 21.5, 45.3, 113.7, 113.8, 120.6, 122.7,125.1, 127.3, 127.7, 129.1, 136.1, 136.2, 143.5, 155.4.

[0050] Analysis: Calculated data for C₁₆H₁₅NO₃S: C, 63.77; H, 5.02;N,4.65.

[0051] Measured data: C, 61.11; H, 5.32; N, 4.31.

[0052] Process 4

[0053] In argon atmosphere, the dimethylsulfoxide solution (1.5 L)containing the compound 5 (362 g, 0.940 mol) and potassium hydroxide(248 g, 3.76 mol) is stirred at 130° C. for 30 minutes. The reactionmixture is cooled down to room temperature and cooled with ice-bath andacidified with 3 N hydrochloric acid. The obtained mixture is washedwith ethyl acetate three times. Then the water layer is neutralized withsodium hydrogen carbonate, while cooling with ice-bath, and organiccomponent is extracted from the water layer with ethyl acetate 5 to 10times. The obtained organic extracts are dried over magnesium sulfateanhydride, and the solvent is condensed by vacuum. The obtained crudematerial is recrystallized from ethanol to obtain 101.5 g (72%, 4 steps)of 7-hydroxyquinoline (compound 2).

[0054] The reaction can be indicated by the following scheme.

[0055] Physical Property

[0056] IR (film, cm⁻¹) 3423, 1610, 1503, 1336, 1293, 1162, 1089, 811,690, 656, 582, 562, 544.

[0057]¹H NMR (400 MHz, DMSO-d₆): δ 7.17 (1H, dd, J=2.0, 8.8 Hz), 7.25(1H, dd, J=5.2, 8.8 Hz), 7.28 (1H, d, J=2.8 Hz), 7.78 (1H, d, J=8.8 Hz),8.16 (1H, d, J=8.0 Hz),8.73 (1H, dd, J=2.0, 5.2 Hz), 10.2 (1H, s).

[0058]¹³C NMR (100 MHz, DNSO-d₆): δ 110.0, 118.4, 119.3, 122.3, 129.3,135.6, 149.5, 150.5, 158.5.

[0059] Analysis: Calculated data for C₉H₇NO: C, 74.47; H, 4.86; N, 9.65.

[0060] Measured data: C, 74.28; H, 5.08; N, 9.49.

Example 2

[0061] The experimental results of the following reaction based on thepresent invention are shown.

[0062] The compound 6 is dissolved in dichloromethane and TfOH (3.8 μL,0.043 mmol) is added via a syringe under argon atmosphere at roomtemperature. The obtained mixture is stirred under argon atmosphere at50° C. for 20 minutes. The reaction mixture is diluted with ethylacetate and washed with saturated sodium bicarbonate. The separatedwater phase is extracted by ethyl acetate twice. The combined organicphase is washed with brine, dried over magnesium sulfate anhydride,filtrated, and condensed to give a crude product. The crude product ispurified by a silica gel column chromatography by elution with 40% ethylacetate/hexane to obtain dihydroquinoline derivative 7 (78 mg, 80%).

[0063] Physical Property

[0064] IR (film, cm⁻¹): 2930, 1490, 1346, 1336, 1158, 1065, 964, 824,760.

[0065]¹H NMR (400 MHz, CDCl₃): δ 2.34 (s, 3H), 2.69 (s, 3H), 4.39 (m,2H), 6.00-6.03 (m, 1H), 6.57 (d, J=10.0 Hz, 1H), 6.96 (s, 1H), 7.08 (d,J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H).

[0066]¹³C NMR (100 MHz, CDCl₃): δ 20.9, 37.5, 45.4, 124.6, 126.4, 127.1,127.4, 128.8, 129.1, 136.8.

[0067] HR-MS (EI) Calculated data for C₁₁H₁₃NO₂S: 223.0667.

[0068] Measured data: 223.0664.

Examples 3-9

[0069] Consideration about the effect of substituted group toregioselectivity and yield in the method for preparation of quinolinesof the present invention.

[0070] The method and results for the preparation of quinolines by wayof mentioned cyclization reaction of meta- or 3,4-substituted anilinederivatives are summarized in Table 1. In Table 1, Ms=mesyl group,p-Ts=para-toluenesulfonyl group, Tf=trifluoromethanesulfonyl group,THF=tetrahydrofuran. TABLE 1 Exam- Acid Temp. Time Yield Ratio ple R₁ R₂R₄ (equivalent) Solvent (° C.) (min.) (%) (A:B) 3 H MeO Ms 3N HCl THF 8020 85 8:1 4 H MeO p-Ts 3N HCl THF 80 40 94 13:1  5 H OH p-Ts 3N HCl THF80 20 82 14:1  6 MeO MeO Ms TfOH (0.1) CH₂Cl₂ 50 10 84 1:0 7 H Br p-TsTfOH (1.0) CH₂Cl₂ rt 10 88 3:1 8 H Br p-Ts TfOH (1.0) CH₂Cl₂ rt 10 855:1 9 Cl Cl Ms TfOH (1.0) CH₂Cl₂ rt 10 36 2:1

[0071] According to the ratio of regioisomers (A:B), it is clearlyunderstood that the regioselectivity of reaction is remarkably improvedcompared with the conventional method for synthesis, and further, yieldsare remarkably improved.

Example 10

[0072]

[0073] As shown by above mentioned scheme, palladium on carbon (10 wt. %on activated carbon) (280 mg) is added to ethanol solution (35 ml) ofcompound 8 (2.79 g, 4.32 mmol) and stirred under hydrogen atmosphere for6 hours. The suspension is filtrated through a pad of celite and thefilter cake is then rinsed with ethanol. Without condensation of thereacted solution, formalin (5.2 ml, 65 mmol), dimethylaminehydrochloride (3.6 g, 43 mmol), sodium acetate (3.8 g, 45 mmol), andacetic acid (1.4 ml, 24 mmol) are added sequentially while cooling withice-bath. After elevating the temperature to room temperature, themixture was stirred at said temperature for 3 hours to overnight. Afterthe reaction completes, the mixture is diluted by diethylether andwashed with aqueous saturated sodium bicarbonate and brine. The organiclayer is dried over magnesium sulfate anhydride, and solvent iscondensed by vacuum. The residue is purified by silica gel columnchromatography to obtain 91.93 g (85%) of aimed product from elutionpart using mixing solution of hexane:ethylacetate=5:1.

[0074] Physical Property:

[0075] IR (film, cm⁻¹): 3354, 2952, 1730, 1613, 1475, 1442, 1364, 1330,1184, 1153, 1097, 967, 835, 758, 529.

[0076]¹H NMR (400 MHz, SDCl₃): δ 1.37-1.69 (6H, m), 1.53 (9H, s), 2.89(2H, m), 3.09 (3H, s), 3.37 (1H, m), 3.51 (1H, q, J=6.8 Hz), 3.66 (3H,s), 3.62-3.68 (1H, m), 3.86 (1H, m), 4.50 (1H, s), 5.87 (1H, s), 6,57(1H, d, J=2.0 Hz), 7.11(1H, dd, J=2.0, 7.6 Hz), 7.55 (1H, d, J=8.8 Hz),8.06 (1H, d, J=1.6 Hz)

[0077]¹³C NMR (100 MHz, CDCl₃): δ 14.2, 19.5, 25.2, 25.3, 27.8, 30.5,37.2, 52.1, 62.2, 67.1, 85.1, 99.0, 109.8, 116.8, 118.5, 120.4, 128.6,128.8, 133.3, 134.0, 135.6, 146.8, 149.7, 166.2.

[0078] For measurements, JASCO FT/IR-410, which is the product of NihonBunko Co., Ltd., is used as IR spectromater and JEOL-LA400 of NihonDenshi Co., Ltd., is used as a nuclear magnetic resonance spectromater.

Reference Example Illustration of Usefulness of Intermediate A Obtainedby the Present Invention

[0079] The method for synthesis of vindoline, which is a usefulapplication of the compound obtained by the method of the presentinvention, will be illustrated as follows.

[0080] To the methanol solution (200 ml) of above mentioned compound 9(7.4 g, 14 mmol) and (1S)-(+)-camphorsulfonic acid (7.3 g, 28.2 mmol)are added while cooling with ice-bath, and the resulting mixture isstirred for 2 hours. The reaction mixture is diluted by ethyl acetate,and washed with saturated sodium bicarbonate and brine. The organiclayer is dried over magnesium sulfate anhydride, and solvent iscondensed by vacuum. The residue is recrystallized from ethyl acetate togive the compound of general formula F. To a benzene solution (132 ml)containing compound 10 (6.67 g, 15.2 mmol), chiral amine(DNs=2,4-dinitrobenzenesulfonyl), and triphenylphosphine (6.30 g, 22.8mmol) is added diethylazodicarboxylate (DEAD, 10.3 ml, 22.8 mol) (40%toluene solution) dropwise while cooling with ice-bath, the temperatureis then elevated to room temperature. After stirring for an hour, thereaction mixture is diluted with ethyl acetate and washed with brine.The organic layer is dried over magnesium sulfate anhydride, and solventis condensed by vacuum. The residue is purified by silica gel columnchromatography by elution with n-hexane:ethyl ether=1:2 mixed solutionto obtain compound 12 as yellowish powder.

[0081] To the dichloromethane solution of said compound 12 was addeddimethylsulfide (Me₂S) at room temperature and the resulting mixture isstirred for 5 minutes maintaining same temperature, and then trifluoroacetic acid (TFA) is added dropwise. After stirring at said temperaturefor 5 minutes, the reaction mixture is added into the saturated sodiumbicarbonate while cooling with ice-bath. The water phase is extractedtwice by ethyl acetate and then twice by dichloromethane, then theextracted solutions are combined. After dried over magnesium sulfateanhydride, the solution is filtrated and condensed by vacuum. Theobtained residue is dissolved in acetonitrile and methanol, to which isadded pyrrolidine dropwise with cooling with ice-bath. After stirringfor 5 minutes at room temperature, the temperature is elevated to 70° C.and the mixture was stirred another 3 hours. After cooling the reactionmixture to room temperature, the mixture is diluted with diethyl etherand washed twice with brine. The organic layer is dried over magnesiumsulfate anhydride, the solvent is condensed by vacuum. Then the residueis purified by silica gel column chromatography by elution withn-hexane:ethyl acetate:methanol=100:50:3 mixed solution to obtaincompound 13 as white powder [precursor compound of (−)-vinhydoline].

[0082] Synthetic Reaction of Vindoline by Use of the Intermediate of thePresent Invention.

Reference Example 2

[0083] For the illustration of the usefulness of the method forsynthesis of quinolines of the present invention, a synthetic example ofcompound (compound 17) represented by general formula A from quinoline(compound 13) is shown as follows.

[0084] The compound 17 is synthesized by following reactions. That is,ring-opening reaction of quiniline 13 by thiophosgene, formation ofisothiocyanate, synthesis of compound 16 by nucleophilic additionreaction of malonic acid derivatives to compound 15, and reaction ofcompound 16, tri-n-butyltin hydride and 2,2′-azobisisobutyronitrile intoluene solution.

[0085] Industrial Applicability

[0086] As mentioned above, by the synthetic route of compoundrepresented by general formula B, not only the yield is improved to 85%,but also the excellent effect that the toxicity of reagent used in saidsynthesis is smaller compared with that of above mentioned conventionalart is brought. Further, the substituted quinolines represented bygeneral formula C, which is the starting compound for the synthesis ofthe compound of general formula A, can be synthesized by formation ofsulfonamide derivative of said substituted aniline represented bygeneral formula E, addition of the sulfoamide to acrolein to lead thecompound of general formula D, and cyclization reaction of the compoundof general formula D. According to this process, the excellent functionand effect that the regioselectivity and yield of the obtained compoundare improved and the work-up procedure and purification process afterthe reaction is simplified can be brought.

What is claim
 1. A compound represented by general formula A useful as an intermediate at the total synthesis of vindoline,

wherein, R¹ is one selected from the group consisting of H, OH, alkoxy group, substituted or non-substituted benzenesulfonyloxy group and alkyl sulfonyloxy group, R² is (1,1-dimethylethoxy)carbonyl group or acetyl group, R³ is alkyl group, R⁴ is benzyl or substituted benzyl group and R⁵ is H, tetrahydropyranyl (THP) group, ethoxyethyl group, methoxymethyl group, acetyl group, benzoyl group, trialkylsilyl group or alkyldiarylsilyl group.
 2. A method for synthesis of indole derivatives, which are useful for the synthesis of vindoline, represented by general formula B comprising, hydrogenation of the compound represented by general formula A, transforming benzyl ester to carboxylic acid, and then formation of an acrylic acid alkyl ester unit by Mannich reaction accompanied with decarboxylation under the condition of Mannich reaction,

wherein, R¹ is one selected from the group consisting of H, OH, alkoxy group, substituted or non-substituted benzenesulfonyloxy group, and alkylsulfonyloxy group, R² is (1,1-dimethylethoxy) carbonyl group or acetyl group, R³ is alkyl group and R⁵ is H, tetrahydropyranyl group, ethoxyethyl group, methoxymethyl group, acetyl group, benzoyl group, trialkylsilyl group or alkyldiarylsilyl group.
 3. The method for synthesis of indole derivatives, which are useful for the synthesis of vindoline, represented by general formula B of claim 2 comprising, using palladium on carbon catalyst prepared by loading palladium on activated carbon as a hydrogenation catalyst.
 4. A method for synthesis of the substituted quinoline represented by general formula D,

by reacting sulfonamide derivative of substituted aniline represented by general formula E,

wherein R₁, R₂ and R₃ is selected independently from the group consisting of H, OH, alkoxy group, alkyl group, amino group, amino group, and halogen, R₄ is alkyl group or substituted or non substituted benzene, in alcohol containing acrolein and triethylamine so as to synthesize aldehyde intermediate represented by general formula D,

then cyclizing said aldehyde intermediate by trifluoromethanesulfonic acid or under the acidic condition and obtaining dihydroquinoline derivatives represented by general formula F,

then treating the obtained dihydroquinoline derivative in MOH, wherein M is Na or K, in DMSO.
 5. The method for synthesis of substituted quinoline of claim 4, wherein R₁ is a substituted group of 7-position, R₂ is a substituted group of 6-position and each substituted group is respectively selected from the group consisting of H, hydroxyl group, alkoxy group and halogen independently and R₃ is H.
 6. The method for synthesis of substituted quinoline of claim 5, wherein the cyclization reaction is carried out in tetrahydrofuran solution in which hydrochloric acid of stronger than 3N is contained. 